Regulation of Cyclooxygenase-2 and Periostin by Wnt-3 in Mouse Mammary Epithelial Cells

Marion Haertel-Wiesmann,Yuxin Liang,Wendy J Fantl,Lewis T Williams

doi:10.1074/jbc.m000074200

Abstract

Wnt family members are critical in developmental processes and have been shown to promote carcinogenesis when ectopically expressed in the mouse mammary gland. The gene expression pattern mediated by Wnt is pivotal for these diverse responses. The Wnt pathway has been conserved among different species. Genetic studies have shown that Wnt effects are mediated, at least in part, by beta-catenin, which regulates transcription of "downstream genes." Wnt stimulation inactivates glycogen-synthase kinase-3beta (GSK-3) with subsequent stabilization of beta-catenin, which after heterodimerizing with lymphocyte enhancer factor-1/T-cell factor cofactors stimulates transcription. To establish whether Wnt-stimulated transcription is mediated solely by beta-catenin, a comparison was made of gene expression profiles in response to Wnt-3, overexpression of beta-catenin, and inhibition of GSK-3. Infection of cells with Wnt-3 and inhibition of GSK-3 regulate a set of genes that include cyclooxygenase-2 and periostin. Interestingly, overexpression of beta-catenin or reducing beta-catenin levels with antisense oligonucleotide transfection did not have any effect on cyclooxygenase-2 or periostin expression, thereby defining a Wnt pathway, which cannot be mimicked by beta-catenin overexpression.

Highlights

The Wnt proteins are a family of secreted cysteine-rich glycoproteins that play an essential role in directing developmental processes such as cell adhesion, cell fate, and cell proliferation [1, 2]
Wnt family members are critical in developmental processes and have been shown to promote carcinogenesis when ectopically expressed in the mouse mammary gland
Overexpression of ␤-catenin or reducing ␤-catenin levels with antisense oligonucleotide transfection did not have any effect on cyclooxygenase-2 or periostin expression, thereby defining a Wnt pathway, which cannot be mimicked by ␤-catenin overexpression

Summary

Introduction

The Wnt proteins are a family of secreted cysteine-rich glycoproteins that play an essential role in directing developmental processes such as cell adhesion, cell fate, and cell proliferation [1, 2]. A number of potential Wnt-1 target genes have been identified in different organisms, including ultrabithorax and engrailed in Drosophila [9, 10], nodal-related 3 and siamois in Xenopus [11,12,13], Connexin 43 [14], Wisp [15], cyclin D1 [16], and Cox-2 [17] in various mammalian cell lines or tissues. It is not clear whether the entire transcriptional response to the stimulation by Wnt-1 or Wnt-3 is mediated by ␤-catenin-dependent processes. The data show that the genes regulated by Wnt-3 involve multiple pathways downstream of GSK-3, not all of which are dependent on ␤-catenin

Methods

Results

Conclusion